The dopamine receptor D₄ is a dopamine D2-like

G protein-coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related ...

encoded by the gene on chromosome 11 at 11p15.5. The structure of DRD4 has been reported in complex with the antipsychotic drug nemonapride. As with other dopamine receptor subtypes, the D₄ receptor is activated by the

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

. It is linked to many neurological and psychiatric conditions including

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

and

bipolar disorder Bipolar disorder (BD), previously known as manic depression, is a mental disorder characterized by periods of Depression (mood), depression and periods of abnormally elevated Mood (psychology), mood that each last from days to weeks, and in ...

ADHD Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by symptoms of inattention, hyperactivity, impulsivity, and emotional dysregulation that are excessive and pervasive, impairing in multiple ...

, addictive behaviors,

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

, and

eating disorders An eating disorder is a mental disorder defined by abnormal eating behaviors that adversely affect a person's health, physical or mental health, mental health. These behaviors may include eating too much food or too little food. Types of eatin ...

such as

anorexia nervosa Anorexia nervosa (AN), often referred to simply as anorexia, is an eating disorder characterized by Calorie restriction, food restriction, body image disturbance, fear of gaining weight, and an overpowering desire to be thin. Individuals wit ...

. A weak association has been drawn between DRD4 and

borderline personality disorder Borderline personality disorder (BPD) is a personality disorder characterized by a pervasive, long-term pattern of significant interpersonal relationship instability, an acute fear of Abandonment (emotional), abandonment, and intense emotiona ...

. It is also a target for drugs which treat

and

. The D₄ receptor is considered to be D₂-like in which the activated receptor inhibits the enzyme

adenylate cyclase Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction: :A ...

, thereby reducing the intracellular concentration of the second messenger

cyclic AMP Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger, or cellular signal occurring within cells, that is important in many biological processes. cAMP is a derivative of adenosine triph ...

Genetics

The human protein is coded by the ''DRD4'' on chromosome 11 located in 11p15.5. There are slight variations (

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...

s/ polymorphisms) in the human gene: * A 48-base pair VNTR in

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...

3 * C-521T in the promoter * 13-base pair deletion of bases 235 to 247 in exon 1 * 12 base pair repeat in exon 1 * Val194Gly * A polymorphic tandem duplication of 48 bp Mutations in this gene have been associated with various behavioral phenotypes, including autonomic nervous system dysfunction,

attention deficit/hyperactivity disorder Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by symptoms of inattention, hyperactivity, impulsivity, and emotional dysregulation that are excessive and pervasive, impairing in multiple con ...

Gene Overview of All Published Schizophrenia-Association Studies for DRD4
– SzGene database at Schizophrenia Research Forum. and the personality trait of

novelty seeking In psychology, novelty seeking (NS) is a personality trait associated with exploratory activity in response to novel stimulation, impulsive decision making, extravagance in approach to reward cues, quick loss of temper, and avoidance of frustrati ...

48-base pair VNTR

The 48-base pair variable number tandem repeat ( VNTR) in

3 range from 2 to 11 repeats. Dopamine is more potent at the D4 receptor with 2 allelic repeat or 7 allelic repeats than the variant with 4 allelic repeats. DRD4-7R, the 7-repeat (7R) variant of ''DRD4'' (DRD4 7-repeat polymorphism), has been linked to a susceptibility for developing

in several meta-analyses and other psychological traits and disorders. Adults and children with the DRD4 7-repeat polymorphism show variations in auditory-evoked gamma oscillations, which may be related to attention processing. The frequency of the alleles varies greatly between populations, e.g., the 7-repeat version has high incidence in America and low in Asia. "Long" versions of polymorphisms are the alleles with 6 to 10 repeats. 7R appears to react less strongly to dopamine molecules. The 48-base pair VNTR has been the subject of much speculation about its evolution and role in human behaviors cross-culturally. The 7R allele appears to have been selected for about 40,000 years ago. In 1999 Chen and colleagues observed that populations who migrated farther in the past 30,000 to 1,000 years ago had a higher frequency of 7R/long alleles. They also showed that nomadic populations had higher frequencies of 7R alleles than sedentary ones. More recently it was observed that the health status of nomadic Ariaal men was higher if they had 7R alleles. However, in recently sedentary (non-nomadic) Ariaal those with 7R alleles seemed to have slightly deteriorated health.

Novelty seeking

Despite early findings of an association between the ''DRD4'' 48bp VNTR and

(a normal characteristic of exploratory and excitable people), a 2008

meta-analysis Meta-analysis is a method of synthesis of quantitative data from multiple independent studies addressing a common research question. An important part of this method involves computing a combined effect size across all of the studies. As such, th ...

compared 36 published studies of novelty seeking and the polymorphism and found no effect. Results are consistent with novelty-seeking behavior being a complex trait associated with many genes, and the variance attributable to ''DRD4'' by itself being very small. The meta-analysis of 11 studies did find that another polymorphism in the gene, the -521C/T, showed an association with novelty seeking. While human results are not strong, research in animals has suggested stronger associations and new evidence suggests that human encroachment may exert selection pressure in favor of ''DRD4'' variants associated with novelty seeking.

Cognition

Several studies have shown that

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

s that activate the D4 receptor increase working memory performance and fear acquisition in monkeys and rodents according to a U-shaped dose response curve. However,

antagonists An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain. Gamma oscillations, which may be correlated with cognitive processing, can be increased by D4R agonists, but are not significantly reduced by D4R antagonists.

Cognitive development

Several studies have suggested that parenting may affect the

cognitive development Cognitive development is a field of study in neuroscience and psychology focusing on a child's development in terms of information processing, conceptual resources, perceptual skill, language learning, and other aspects of the developed adult bra ...

of children with the 7-repeat allele of ''DRD4''. Parenting that has maternal sensitivity, mindfulness, and autonomy–support at 15 months was found to alter children's executive functions at 18 to 20 months. Children with poorer quality parenting were more impulsive and sensation seeking than those with higher quality parenting. Higher quality parenting was associated with better executive control in 4-year-olds.

Ligands

Agonists

* WAY-100635: potent full

, with 5-HT_1A antagonistic component * A-412,997: full agonist, > 100-fold selective over a panel of seventy different receptors and ion channels * ABT-724 - developed for treatment of erectile dysfunction * ABT-670 - better oral bioavailability than ABT-724 * FAUC 316: partial agonist, > 8600-fold selective over other dopamine receptor subtypes * FAUC 299: partial agonist * F-15063: antipsychotic with partial D4 agonism * (''E'')-1-aryl-3-(4-pyridinepiperazin-1-yl)propanone oximes * PIP3EA: partial agonist * Flibanserin - partial agonist * PD-168,077 - D₄ selective but also binds to α1A, α2C and 5HT_1A * CP-226,269 - D₄ selective but also binds to D₂, D₃, α2A, α2C and 5HT_1A * Ro10-5824 – partial agonist * Roxindole – D₄ selective but also D₂ and D₃ autoreceptor agonist, 5HT_1A receptor agonist,

serotonin reuptake inhibitor A serotonin reuptake inhibitor (SRI) is a type of drug which acts as a reuptake inhibitor of the neurotransmitter serotonin (5-hydroxytryptamine, or 5-HT) by blocking the drug action, action of the serotonin transporter (SERT). This in turn lea ...

) * Apomorphine – D₄ selective but also D₂ and D₃ agonist, α-

adrenergic Adrenergic means "working on adrenaline (epinephrine) or noradrenaline (norepinephrine)" (or on their receptors). When not further qualified, it is usually used in the sense of enhancing or mimicking the effects of epinephrine and norepinephrine ...

and serotonergic weak antagonist * Nuciferine - D₄ full selective but also partial D₂ and D₅ agonist

Antagonists

* A-381393: potent, subtype selective antagonist (>2700-fold) * FAUC 213 * L-745,870 * L-750,667 * ML-398 * S 18126 - also σ₁ affinity * Fananserin – mixed 5-HT_2A / D₄ antagonist *

Olanzapine Olanzapine, sold under the brand name Zyprexa among others, is an atypical antipsychotic primarily used to treat schizophrenia and bipolar disorder. It is also sometimes used off-label for treatment of chemotherapy-induced nausea and vomitin ...

, an atypical antipsychotic *

Buspirone Buspirone, sold under the brand name Buspar among others, is an anxiolytic, a medication primarily used to treat anxiety disorders, particularly generalized anxiety disorder (GAD). It is a serotonin 5-HT1A receptor, 5-HT1A receptor partial ag ...

, an anxiolytic

Inverse agonists

* FAUC F41:

inverse agonist In pharmacology, an inverse agonist is a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist. A neutral antagonist has no activity in the absence of an agonist or inverse agon ...

, subtype selectivity of more than 3 orders of magnitude over D₂ and D₃

In popular culture

Michael Connelly Michael Joseph Connelly (born July 21, 1956) is an American author of Detective fiction, detective novels and other crime fiction, notably those featuring Los Angeles Police Department, LAPD Detective Harry Bosch, Hieronymus "Harry" Bosch and cr ...

’s 2020 crime novel '' Fair Warning'' (ISBN 978-0-316-53942-5) revolves around a serial killer who uses DNA profiles obtained on the

Dark Web The dark web is the World Wide Web content that exists on darknets ( overlay networks) that use the Internet but require specific software, configurations, or authorization to access. Through the dark web, private computer networks can communica ...

to target female victims, specifically those whose DRD4 profiles allegedly make them more susceptible to risk taking and sexual promiscuity.

References

External links

*
Current Research on the DRD₄ Gene
* * * * {{DEFAULTSORT:Dopamine Receptor D4 Dopamine receptors Biology of attention deficit hyperactivity disorder Genes on human chromosome 11